In addition to a classic role in homeostatic regulation of blood pressure and fluid balance, components of the Renin Angiotensin System (RAS) have also been implicated in tissue remodeling and wound repair. RAS is present in virtually every organ system and a local and independently regulated RAS in human monocytes has been identified. The binding of Angiotensin II, the main RAS effector hormone, to the angiotensin II type 1 receptor (AT1R) increases the production of the inflammatory molecules and regulates multiple steps in the inflammatory process. Inappropriate activation of the RAS may contribute to chronic inflammation.
The etiologies of aberrant RAS activation are not known. Autoantibodies that react with the AT1R (AT1RaAbs) and increase expression and function of the receptor in an apparent positive feedback loop have been previously identified in pre-eclampsia. AT1RaAbs have also been linked to transplant rejection and malignant hypertension. A pro-inflammatory cascade has been proposed that comprises antibody binding, signal transduction through ERK1/2, an increase in reactive oxygen species, NADPH oxidase expression, and nuclear factor-kappa B (NFκB) activation. Activation of this pro-inflammatory pathway has been suggested as a potential mechanism for endothelial damage observed in persons with hypertension and cardiovascular disease.
Older adults who are particularly vulnerable to a host of adverse health outcomes including falls, functional decline, disability, multimorbidity and early mortality exhibit a frailty phenotype that can be identified using a validated clinical tool. Substantial evidence supports the association of chronic inflammation with this older at-risk population. Levels of IL-6 and neutrophil, monocyte and total white blood cell counts are significantly correlated with aggregate risk in older populations. Contributory factors to sustained inflammatory activation are not well defined, but multiple chronic disease states, redox imbalance, senescent cells, and increased body fat have been suggested.
Angiotensin receptor blockers (ARBs) provide cardiovascular protection, in part, through their vascular and anti-inflammatory effects. However, their efficacy and utility in the presence of AT1RaAb is unknown. There exists a need to investigate the effects of AT1RaAb in the therapeutic usage of ARBs. Likewise, there is a need to develop improved therapeutic methods that can take advantage of a patient's levels of AT1RaAb.